Evaluation of methylthio-, methylsulfinyl-, and methylsulfonyl- analogs of alkanes and alkanoic acids as cardiac inotropic and antifungal agents

Article abstract of DOI:10.1002/1521-4184(20009)333:9<293::AID-ARDP293>3.0.CO;2-2

A group of alkane and alkanoic acid compounds of general formula MeS(O)(m)(CH₂)(n)R [m = 0 - 2; n = 1, 5, 13; R = Me, CO₂H(Na)] were synthesized for evaluation as cardiac inotropic and antifungal agents. Inotropic activity was determined as the ability of the test compound to modulate in vitro guinea pig atrium contractility. The oxidation state of the S-atom was an important determinant of inotropic modulation since the thio (m = 0) analogs exhibited a positive inotropic effect. In contrast, the sulfonyl (m = 1) and sulfonyl (m = 2) analogs exhibited a negative inotropic effect. A pentyl spacer (n = 5) provided the largest positive or negative inotropic effect. The relative positive, and negative, inotropic potency orders with respect to the R-substituent were Me ≥ CO₂H, and CO₂Na ≥ Me, respectively. The most potent positive inotrope MeS(CH₂)₅Me (EC₅₀ = 4.49 x 10^-6 M) could serve as a useful lead-compound for the design of a new class of positive inotropic agents. In a broad spectrum antifungal screen, the minimal inhibitory concentration (MIC) range for the five most active compounds was MeSO₂(CH₂)₅Me (0.46-1.83 mM), MeS(CH₂)₁₃Me (0.31-1.23 mM), MeSO(CH₂)₁₃Me (< 0.009-1.87 mM), MeSO₂(CH₂)₁₃Me (0.27-1.09 mM), and MeS(CH₂)₁₃CO₂H (0.27-1.09 mM), relative to the reference drug Ampotericin B (< 0.0002-0.002 mM). The most active antifungal agent MeSO(CH₂)₁₃Me was selective against C. guillermondi, C. neoformans, S. cerevisiae, and A. fumigatus (strain TIMM 1776).

Full text of DOI:10.1002/1521-4184(20009)333:9<293::AID-ARDP293>3.0.CO;2-2

Cardiac Inotropic and Antifungal Agents
293
Evaluation of Methylthio-, Methylsulfinyl-, and Methylsulfonyl-
Analogs of Alkanes and Alkanoic Acids as Cardiac Inotropic and
Antifungal Agents
Nadeem Iqbal, Carol-Anne McEwen, Soroush Sardari, Mohsen Daneshtalab, and Edward E. Knaus*
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8
Key Words: Dialkyl sulfides; dialkyl sulfoxides; dialkyl sulfones; methylthioalkanoic acids; inotropic and antifungal activity
antifungal agents. We now report the in vitro cardiac modu-
lating and antifungal activities for the title compounds.
Summary
A group of alkane and alkanoic acid compounds of generalformula
MeS(O)m(CH2)nR [m = 0 – 2; n = 1, 5, 13; R = Me, CO2H(Na)]
were synthesized for evaluation as cardiac inotropic and antifungal
agents. Inotropic activity was determined as the ability of the test
compound to modulate in vitro guinea pig atrium contractility. The
oxidation state of the S-atom was an important determinant of
inotropic modulation since the thio (m = 0) analogs exhibited a
positive inotropic effect. In contrast, the sulfinyl (m = 1) and
sulfonyl (m = 2) analogs exhibited a negative inotropic effect. A
pentyl spacer (n = 5) provided the largest positive or negative
inotropic effect. The relative positive, and negative, inotropic
potency orders with respect to the R-substituent were Me ≥ CO2H,
and CO2Na ≥ Me, respectively. The most potent positive inotrope
MeS(CH2)5Me (EC50 = 4.49 × 10–6 M) could serve as a useful
lead-compound for the design of a new class of positive inotropic
agents. In a broad spectrum antifungal screen, the minimal inhibi-
tory concentration (MIC) range for the fivemost active compounds
was MeSO2(CH2)5Me (0.46–1.83 mM), MeS(CH2)13Me (0.31–
1.23 mM), MeSO(CH2)13Me (< 0.009–1.87 mM),
MeSO2(CH2)13Me (0.27–1.09 mM), and MeS(CH2)13CO2H
(0.27–1.09 mM), relative to the reference drug Ampotericin B (<
0.0002–0.002 mM). The most active antifungal agent
MeSO(CH2)13Me was selective against C. guillermondi, C. neo-
formans, S. cerevisiae, and A. fumigatus (strain TIMM 1776).
Chemistry
The compounds that were investigated can be categorized
into two groups: a) Sulfide, sulfoxide, and sulfone analogs of
alkanes of general formula MeS(O) (CH ) Me that include
m
2 n
MeSOCH Me (1), MeSO CH Me (2), MeS(CH ) Me (3),
2
2
2
2 5
MeSO(CH ) Me (4), MeSO (CH ) Me (5), MeS(CH ) Me
2 5
2
2 5
2 13
(6), MeSO(CH ) Me (7), and MeSO (CH ) Me (8); and b)
Sulfide, sulfoxide, and sulfone analogs of alkanoic acids of
general formula MeS(O) (CH ) CO Na comprised of
2 13
2
2 13
m
2 n
2
MeSCH CO Na
(20), MeSOCH CO Na
(21),
2
2
2
2
MeSO CH CO Na (22), MeS(CH ) CO Na (23),
2
2
2
2 5
2
MeSO(CH ) CO Na (24), MeSO (CH ) CO Na (25),
2 5
2
2
2 5
2
MeS(CH ) CO H (17), MeSO(CH ) CO Na (27), and
2 13
2
2 13
2
MeSO (CH ) CO Na (28).
2
2 13
2
[5] [6] [7] [8] [9]
[7]
Compounds 1 , 2 , 3 , 4 , 5 , and 6 were prepared
according to the literature procedures. Oxidation of methyl
tetradecyl sulfide (6) with sodium metaperiodate (NaIO ) in
4
H O afforded a mixture of the target product methyl
2
tetradecyl sulfoxide (7), unreacted 6, and an additional prod-
uct that was not characterized. To circumvent the low solu-
bility of 6 in H O, oxidation of 6 using 30% H O (1.2 equiv.)
2
2 2
in EtOH at 35 °C afforded 7 (85% yield). Alternatively,
oxidation of 6 using 30% H O (2.1 equiv.) in HOAc at
2
2
80–90 °C yielded methyl tetradecyl sulfone (8, 80% yield) as
illustrated in Scheme 1.
Introduction
O
A small amount of dimethyl sulfoxide (Me SO) is fre-
2
(a)
quently used as a co-solvent (1–2%, v/v in an aqueous buffer)
to solubilize sparingly soluble organic compounds to be
evaluated using in vitro biological assays. In this respect, we
observed that use of1–2% of dimethyl sulfoxide as co-solvent
induced an in vitro positive inotropic effect on guinea pig left
atrium. Long-chain fatty acids, which undergo β-oxidation
fatty-acid catabolism, are the principal energy source in the
normal heart. Accordingly, long-chain fatty acid analogs
labeled with γ-emitting radionuclides have been evaluated as
Me-S-(CH ) Me
2 13
7
Me-S-(CH ) Me
2 13
O
(b)
6
Me-S-(CH ) Me
2 13
8
O
Scheme 1. Reagents and conditions: (a) 30% H2O2, EtOH, 35 °C, 2 h;
(b) 30% H2O2, HOAc, 80–90 °C, 3 h.
myocardial imaging agents to delineate areas of infarcted and
[1–3]
ischemic tissue and myocardial fatty acid metabolism
. In
an earlier study, we showed that myristic acid (tetradecanoic
acid) analogs exhibit antifungal activity . It was therefore literature procedure . Oxidation of commercially available
Methylsulfinylacetic acid (10) was prepared according to a
[4]
[10]
of interest to evaluate a group of methylthio-, methylsulfinyl-, methylthioacetic acid (9) with 30% H O at 80–90 °C yielded
2
2
and methylsulfonyl- analogs of alkanes, and related alkanoic methylsulfonylacetic acid (11, 80%) as indicated in
acids, with respect to their inotropic effect on heart and as Scheme 2.
Arch. Pharm. Pharm. Med. Chem.
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0365-6233/00/0909/0293 $17.50 +.50/0

294
Iqbal, McEwen, Sardari, Daneshtalab, and Knaus
structure-activity relationship studies was to determine the
O
(a)
effect which the oxidation state of the sulfur atom [-S(O) ,
m
Me-S-CH CO H
Me-S-CH CO H
2
2
2
2
m = 0, 1, 2], the length of the alkyl spacer [-(CH ) , n = 1, 5,
2 n
9
O
11
13], and the nature of the terminal alkyl substituent (R = Me,
CO H (Na)] had on inotropic activity (see results in Table 1).
2
Scheme 2. Reagents and conditions: (a) 30% H2O2 (2.1 equiv.), 80–90 °C,
3 h.
The oxidation state of the S-atom was an important modulator
of inotropic activity since the methylthio (MeS-; 3, 6, 17)
analogs exhibited a positive inotropic effect. In contrast, the
methylsulfinyl (MeSO-; 1, 4, 24, 27) and methylsulfonyl
Reaction of 6-bromohexanoic acid (12), or 14-bromo-
tetradecanoic acid (13) with NaSMe, using a modification to
(MeSO -, 8, 25, 28) analogs all exhibited a negative inotropic
[11]
2
a procedure reported by Liu and Vederas , afforded the
effect. Alkyl spacer chain length [(CH ) ] appears to modu-
2 m
respective 6-methylthiohexanoic acid (14, 80%), or 14-
methylthiotetradecanoic acid (17, 66%) as illustrated in
Scheme 3. Oxidation of the methylthio compound 14, or 17,
late inotropic activity since compounds having a pentyl (m =
5) spacer generally have the greatest modulation effect (3, n
= 5 >> 6, n = 13; 4, n = 5 ≥ 1, n = 1; 24, n = 5 > 27, n = 13;
25, n = 5 ≈ 28, n = 13). The effect of the terminal R-substituent
was variable depending upon whether the compound exhib-
ited a positive, or negative, inotropic effect. Accordingly, the
relative positive inotropic potency order was 6 (R = Me) ≥ 17
with NaIO (1 equiv.) gave the previously reported 6-methyl-
4
[11]
sulfinylhexanoic acid (15) , or 14-methylsulfinyltetrade-
canoic acid (18), respectively. Alternatively, oxidation of 14,
or17, using 30% H O (2.1 equiv.)yielded 6-methylsulfonyl-
2
2
hexanoic acid (16, 87%), or 14-methylsulfonyltetradecanoic
acid (19, 88%), respectively.
(R = CO H). In contrast, the relative negative inotropic
2
potency order was 24 (R = CO Na) ≥ 4 (R = Me), and 28 (R
2
= CO Na) >> 8 (R = Me). These structure-activity relation-
2
O
ships suggest that hexyl methyl sulfide (3, positive inotrope,
(b)
–6
Me-S-(CH )nCO H
2
2
EC = 4.49 × 10 M) may be a useful lead-compound for
50
the design of a positive inotropic agent.
15, n = 5
18, n = 13
(a)
Myristoyl CoA:protein N-myristoyltransferase (NMT) is an
attractive target for the design of antifungal agents. Protein
N-myristoylation refers to the co-translational linkage of
Me-S-(CH )nCO H
Br(CH )nCO H
2
2
2
2
12, n = 5
13, n = 13
O
14, n = 5
17, n = 13
(c)
Me-S-(CH )nCO H
2
2
myristic acid [Me(CH ) CO H], via an amide bond, to the
2 12
2
O
16, n = 5
19, n = 13
H N-terminal glycine (Gly) residues of a variety of fungal
2
Table 1. In vitro inotropic effect of methylthio-, methylsulfinyl-, and methyl-
sulfonyl- analogs of alkanes (1, 3, 4, 6, 8), and alkanoic acids or their sodium
salts (17, 24–25, 27–28), on the contractile response of guinea pig left atrium.
Scheme 3. Reagents and conditions: (a) NaSMe, MeOH, reflux, 6 h; (b)
NaIO4, MeOH, 0 °C, 12 h; (c) 30% H2O2 (2.1 equiv.), 80–90 °C, 2 h.
——————————————————————————————
MeS(O)m(CH2)nR
The alkanoic acid sodium salts (20–28) were prepared by
treatment of the respective acids (9–11, 14–19) with one
equivalent of NaOH in aqueous EtOH as illustrated in
Scheme 4.
Compd
m
n
R
% Inotropic effect[a]
——————————————————————————————
1
3
1
0
1
0
2
0
1
2
1
2
1
5
Me
–20.7 ± 10.8
+234 ± 122[b]
–30.2 ± 4.1
+21.7 ± 7.9
–3.0 ± 8.9
Me
(a)
Me-X-(CH2)n-CO2Na
Me-X-(CH2)n-CO2H
, X = S, n = 1
4
5
Me
6
13
13
13
5
Me
, X = S, n = 1
20
9
8
Me
21, X = SO, n = 1
22, X = SO2, n = 1
23, X = S, n = 5
10, X = SO, n = 1
11, X = SO2, n = 1
14, X = S, n = 5
17
24
25
27
28
CO2H
CO2Na
CO2Na
CO2Na
CO2Na
+14.9 ± 10.6
–43.6 ± 5.4
–42.3 ± 10.2
–19.1 ± 7.1
–42.1 ± 1.6
5
24, X = SO, n = 5
25, X = SO2, n = 5
26, X = S, n = 13
27, X = SO, n = 13
28, X = SO2, n = 13
15, X = SO, n = 5
16, X = SO2, n = 5
17, X = S, n = 13
18, X = SO, n = 13
19, X = SO2, n = 13
13
13
——————————————————————————————
[a]The % increase in the tonic contractile response (+ % increase ± SEM, n
=3; positive inotropic effect), or the % decrease in the tonic contractile
response (– % decrease ± SEM, n = 3; negative inotropic effect), of guinea
pig ileum left atrium, relative to its basal contractile response in the absence
of test compound, was determined at a test compound concentration of
4.47 × 10–5 M.
Scheme 4. Reagents and conditions: (a) NaOH, EtOH, H2O, 25 °C, 1 h.
Results and Discussion
[b] The test compound concentration required to increase the contractile force
by 50%, relative to the basal contractile force in the absence of test com-
pound, was 4.49 × 10–6 M (as determined from a dose-response curve using
twelve test compound concentrations over a concentration range of 1.63 ×
10–10 to 4.47 × 10–5 M, n = 3).
The in vitro cardiac inotropic activities exhibited by a group
of alkane (1, 3, 4, 6, 8) and alkanoic acid (17, 24–25, 27–28)
derivatives of the general formula MeS(O) (CH ) R were
m
2 n
investigated by measurement of their ability to modulate
guinea pig left atrium contractility. The objective of these
Arch. Pharm. Pharm. Med. Chem. 333, 293–298 (2000)

Cardiac Inotropic and Antifungal Agents
295
proteins that is catalyzed by NMT (E.C. 2.3.1.97). These
fungal myristoylated proteins include ADP ribosylation fac-
tor (Arflp.Ar2p) in Candida albicans, Saccharomyces cere-
These five compounds (5–8, 17) were then subjected to a
large panel antifungal screen using a variety of species and
strains for Candida (albicans, tropicalis, krusei, kefyr,
guillermondi, glabrata, neoformans), Saccharomyces (cere-
visiae), and Aspergillus (fumigatus, niger) as illustrated by
the results listed in Table 3. In this screen, the minimum
inhibitory concentration (MIC) range for each compound
[12]
visiae, and Cryptococcus neoformans . Accordingly,
myristic acid analogs, that act as inhibitors of protein synthe-
sis, block protein N-myristoylation. The observation that
fungal growth can be inhibited by perturbation of the myris-
toylation process, using modified myristic acid analogs, sug-
gests that the enzyme responsible for this protein
modification could provide a plausible target for therapeutic
encompassing all species and strains was MeSO (CH ) Me
2
2 5
(0.46–1.83 mM), MeS(CH ) Me (0.31–1.23 mM),
2 13
MeSO(CH ) Me (< 0.009–1.87 mM), MeSO (CH ) Me
2 13
2
2 13
(0.27–1.09 mM), and MeS(CH ) CO H (0.27–1.09 mM),
[12]
2 13
2
agents . In this regard, a variety of antifungal myristic acid
relative to the reference drug Ampotericin B (< 0.0002–
0.002 mM). The data presented in Table 2 reveals a direct
relationship between antifungal activity and lipophilicity.
Thus, lipophilic compounds 1–8 and 17 exhibited a reason-
able broad spectrum of antifungal activity against yeasts and
molds, whereas the ionic compounds 20–25 and 27–28 were
almost inactive. Among the active compounds, the differ-
ences in antifungal potency were generally small, except for
analogs, possessing halogen, azide, oxygen, sulfur, and aro-
[13–16]
matic substituents, have been reported
.
A group of alkane (1–8) and alkanoic acid (17, 20–25,
27–28) analogs that could act as putative inhibitors of
N-myristoylation were initially tested in vitro for activity
against yeasts (Candida albicans, Cryptococcus neoformans,
Saccharomyces cerevisiae) and filamentous fungi (Aspergil-
lus niger). The results from this preliminary screen (see
results in Table 2) indicated that, among the compounds
MeSO(CH ) Me (7), which showed strong activity against
2 13
different strains of C. neoformans, C. guillermondi, and S.
cerevisiae. Although the mechanism of action of these com-
pounds is not clear at present, we speculate that
tested, MeSO (CH ) Me (5), MeS(CH ) Me (6),
2
2 5
2 13
MeSO(CH ) Me (7), MeSO (CH ) Me (8), and
2 13
2
2 13
MeS(CH ) CO H (17) are the most active antifungal
MeSO(CH ) Me (7) may exhibit its antifungal activity by a
2 13
2
2 13
agents.
dual mechanism. These mechanisms include a general mode
Table 2. Structures and antifungal activity (MIC value, µg/ml)[a] against Candida albicans, Cryptococcus neoformans,
Saccharomyces cerevisiae, and Aspergillus niger for alkanes (1–8) and alkanoic acid (20–28) analogs.
———————————————————————————————————————————————————
Compd
Structure
C. albicans
C. neoformans
S. cerevisiae
A. niger
ATCC 14053
KF-33
PLM 454
PLM 1140
———————————————————————————————————————————————————
1
2
MeSOCH2Me
300
75
75
150
MeSO2CH2Me
300
75
150
150
3
MeS(CH2)5Me
300
75
150
150
4
MeSO(CH2)5Me
MeSO2(CH2)5Me
MeS(CH2)13Me
300
75
150
150
5
300
37.5
75
150
6
300
37.5
150
150
7
MeSO(CH2)13Me
MeSO2(CH2)13Me
MeSCH2CO2Na
150
< 2.34
37.5
2.34
75
8
300
37.5
150
20
21
22
23
24
25
17[c]
27
28
Inactive[b]
Inactive
Inactive
Inactive
Inactive
Inactive
300
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
75
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
75
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
300
MeSOCH2CO2Na
MeSO2CH2CO2Na
MeS(CH2)5CO2Na
MeSO(CH2)5CO2Na
MeSO2(CH2)5CO2Na
MeS(CH2)13CO2H
MeSO(CH2)13CO2Na
MeSO2(CH2)13CO2Na
Inactive
Inactive
< 0.31
0.63
Inactive
300
Inactive
Inactive
0.078
2.5
Inactive
Inactive
0.63
Ampotericin B
Fluconazole
< 0.155
0.63
10
——————————————————————————————————————————————————
[a]The result is the average of three separate determinations for a 24 h (Candida), or 48 h (Cryptococcus, Saccharomyces,
Aspergillus) test compound incubation. [b]All compounds listed as inactive showed no activity at 600 µg/ml. [c]The acid 17
was employed since it is surprisingly more soluble in the incubation medium than its sodium salt (26).
Arch. Pharm. Pharm. Med. Chem. 333, 293–298 (2000)

296
Iqbal, McEwen, Sardari, Daneshtalab, and Knaus
Table 3. Antifungal activity (MIC value, mM)[a] against Candida, Cryptococcus, Saccharomyces, and Aspergillus species for alkane analogs (5–8) and
MeS(CH2)13CO2H (17).
—————————————————————————————————————————————————————————————–
MeSO2(CH2)5Me (5) MeS(CH2)13Me (6)
MeSO(CH2)13Me (7) MeSO2(CH2)13Me (8) MeS(CH2)13CO2H (17) Amphotericin B
—————————————————————————————————————————————————————————————–
C. albicans
ATCC 14053
C. albicans
Y01-09
C. albicans
200/175
C. tropicalis
ATCC 13803
C. krusei
ATCC 44507
C. kefyr
ATCC 38296
C. guillermondi
IF 00838
C. glabrata
ATCC 90030
C. neoformans
PLM 589
C. neoformans
KF-33
S. cerevisiae
PLM 454
1.83
1.83
1.83
1.83
1.83
1.83
0.91
1.83
0.91
1.83
0.46
1.83
1.83
1.83
1.83
1.23
1.23
0.61
1.23
1.23
1.23
0.61
1.23
0.61
1.23
0.31
1.23
1.23
1.23
1.23
1.87
1.09
1.09
0.54
1.09
1.09
0.54
0.54
1.09
0.27
0.27
0.27
1.09
1.09
1.09
1.09
1.09
0.27
1.09
1.09
1.09
1.09
0.55
1.09
0.55
1.09
0.27
1.09
1.09
1.09
1.09
< 0.0002
< 0.0002
< 0.0002
< 0.0002
0.0002
0.29
1.87
1.87
1.87
1.87
< 0.0002
< 0.0002
0.0002
< 0.009
1.87
< 0.009
< 0.009
< 0.009
0.58
< 0.0002
< 0.0002
< 0.0002
< 0.0002
< 0.0002
< 0.0002
< 0.0002
A. fumigatus
PLM 112
A. fumigatus
ATCC 13073
A. fumigatus
TIMM 1776
A. niger
0.58
0.036
0.58
PLM 1140
—————————————————————————————————————————————————————————————–
[a]The result is the average value of three separate determinations for a 24 hour (Candida), or 48 hour (Cryptococcus, Saccharomyces, Aspergillus) test
compound incubation.
Methyl Tetradecyl Sulfoxide (7)
of action shared with other compounds of this series such as
a potential fungal membrane interaction, and a plausible
selective intervention of biochemical mechanisms in C. neo-
formans due to inhibition of 1,6-glucan synthase. In conclu-
sion, due to its significant potency against C. neoformans
Hydrogen peroxide (30% w/v, 0.68 g, 6 mmol) was added to a solution of
methyl tetradecyl sulfide (6, 1.22 g, 5 mmol) in EtOH (10 ml) at 5 °C, and
the reaction was allowed to proceed at 35 °C for 2 h with stirring. Removal
of the solvent in vacuo gave a solid which was recrystallized from ether-hex-
ane to afford 7 (1.1 g, 85%); mp 64–65 °C.– IR (KBr): ν 1022 cm–1 (SO).–
1H NMR (CHCl3-d1): δ 0.87 (t, J = 7.0 Hz, 3H, CH2CH3), 1.25–1.82 [m,
24H, (CH2)12CH3], 2.55 (s, 3H, SOCH3), 2.59–2.78 (m, 2H, SOCH2).
strains, MeSO(CH ) Me (7) can be considered as a potential
2 13
lead-compound for the discovery of novel agents used in the
treatment of cryptococcal meningitis in immunosuppressed
patients.
Methyl Tetradecyl Sulfone (8)
Hydrogen peroxide (30% w/v, 1.2 g, 10.5 mmol) was added to a solution
of methyl tetradecyl sulfide (6, 1.22 g, 5 mmol) in HOAc (2 ml) at 0 °C with
stirring. The reaction was allowed to proceed at 80–90 °C for 3 h prior to
cooling to 25 °C, and then neutralization with 1N NaOH. Extraction with
ether (2 × 25 ml), drying the ether extract (Na2SO4), and removal of the
solvent in vacuo gave a residue that was recrystallized from ether-hexane to
afford 8 (1.1 g, 80%); mp 83–84 °C.– IR (KBr): ν 1315, 1120 cm–1 (SO2).–
1H NMR (CHCl3-d1): δ 0.88 (t, J = 7.0 Hz, 3H, CH2CH3), 1.26–1.89 [m,
24H, (CH2)12CH3], 2.89 (s, 3H, SO2CH3), 3.00 (t, J = 7 Hz, 2H, SO2CH2).
Acknowledgments
We are grateful to the Canadian Institutes of Health Research of Canada
(Grant No. MT-8892) for financial support of this research.
Experimental
Melting points were determined using a Thomas-Hoover capillary appa-
ratus and are uncorrected. 1H NMR spectra were recorded on a Bruker
AM-300 spectrometer. The assignment of exchangeable protons (OH) was
confirmed by the addition of [D2]H2O. Infrared spectra were acquired using
a Nicolet 550 Series II Magna FT-IR spectrometer. Microanalyses were
within ± 0.4% of theoretical values for carbon and hydrogen, unless other-
wise stated. 14-Bromotetradecanoic acid (13) was prepared according to a
literature procedure[17]. Methylthioacetic acid (9) and 6-bromohexanoic acid
(12) were purchased from the Aldrich Chemical Co.
Methylsulfonylacetic Acid (11)
Hydrogen peroxide (30% w/v, 1.2 g, 10.5 mmol, 2.1 equiv.) was added to
a solution of methylthioacetic acid (9, 0.53 g, 5 mmol) in HOAc (2 ml) at
0 °C with stirring, and the reaction was allowed to proceed at 80–90 °C for
3 h. After cooling to 25 °C, HOAc was removed in vacuo, and the residue
was recrystallized from EtOAc-hexane to afford 11 (0.55 g, 80%); mp
Arch. Pharm. Pharm. Med. Chem. 333, 293–298 (2000)

Cardiac Inotropic and Antifungal Agents
297
113 °C (lit.[18] mp 115 °C).– IR (KBr): ν 3200–2538 cm–1 (CO2H), 1325,
1134 (SO2).– 1H NMR (CHCl3-d1): δ 3.16 (s, 3H, CH3), 4.02 (s, 2H, CH2),
7.48 (br s, 1H, CO2H).
Methylthioacetic Acid Sodium Salt (20)
Mp 185–186 °C.– Yield 92%.– IR (KBr): ν 1586, 1399 cm–1 (CO2Na).–
1H NMR (H2O-d2): δ 2.20 (s, 3H, CH3S), 3.26 (s, 2H, SCH2).
6-Methylthiohexanoic Acid (14)
Methylsulfinylacetic Acid Sodium Salt (21)
A solution of 6-bromohexanoic acid (12, 1.95 g, 10 mmol) and NaSMe
(1.4 g, 20 mmol) in MeOH (10 ml) was refluxed for 6 h. After cooling to
25 °C, the reaction mixture was poured onto water (100 ml), acidified with
1N HCl to pH 1, and extracted with CHCl3 (3 × 50 ml). Drying the CHCl3
extract (MgSO4), and removal of the solvent gave an oil that was distilled to
yield 14 (1.3 g, 80%); bp 120–122 °C/1 mm.– IR (Film): ν 3120–2500, 1708
cm–1 (CO2H).– 1H NMR (CHCl3-d1): δ 1.39–1.50 (m, 2H, CH2), 1.57–1.71
(m, 4H, -CH2CH2-), 2.09 (s, 3H, CH3S), 2.37 (t, J = 7.4 Hz, 2H, COCH2),
2.50 (t, J = 7.3 Hz, 2H, SCH2), 10.50 (br s, 1H, COOH).
Mp 130–132 °C.– Yield 98%.– IR (KBr): ν 1590, 1400 cm–1 (CO2Na),
1020 (SO).– 1H NMR (H2O-d2): δ 2.75 (s, 3H, CH3S), 4.80 (s, 2H, SCH2).
Methylsulfonylacetic Acid Sodium Salt (22)
Mp 210–211 °C.– Yield 95%.– IR (KBr): ν 1620, 1415 cm–1 (CO2Na),
1320, 1120 (SO2).– 1H NMR (H2O-d2): δ 3.20 (s, 3H, CH3S), 4.85 (s, 2H,
SCH2).
6-Methylthiohexanoic Acid Sodium Salt (23)
14-Methylthiotetradecanoic Acid (17)
Mp 285–288 °C (decomp).– Yield 95%.– IR (neat): ν 1568, 1424 cm–1
(CO2Na).– 1H NMR (H2O-d2): δ 1.32–1.64 [m, 6H, -(CH2)3], 2.07 (s, 3H,
CH3S), 2.15 (t, J = 7.4 Hz, 2H, CH2CO2Na), 2.52 (t, J = 7.4 Hz, 2H, (s, 2H,
SCH2).
Compound 17 was prepared (1.18 g, 66%) using a procedure similar to that
used for the synthesis of 14 described above; mp 56–58 °C (EtOAc).– IR
(KBr):ν 3100–2673, 1705 cm–1 (CO2H).–1H NMR (CHCl3-d1): δ 1.20–1.31
[m, 20H, -(CH2)10], 1.54–1.65 (m, 2H, CH2), 2.10 (s, 3H, CH3S), 2.35 (t, J
= 7.5 Hz, 2H, COCH2), 2.49 (t, J = 7.5 Hz, 2H, SCH2).
6-Methylsulfinylhexanoic Acid Sodium Salt (24)
14-Methylsulfinyltetradecanoic Acid (18)
Mp 165–166 °C.– Yield 98%.– IR (neat): ν 1568, 1419 cm–1 (CO2Na),
1009 (SO).– 1H NMR (H2O-d2): δ 1.39–1.78 [m, 6H, -(CH2)3], 2.19 (t, J =
7.3 Hz, 2H, CH2CO2Na), 2.68 (s, 3H, CH3SO), 2.84–2.87 (m, 2H, 2H,
SOCH2).
A solution of 17 (0.274 g, 1 mmol) in MeOH (3 ml) at 0 °C was allowed
to react with aqueous NaIO4 (2 ml of 0.5 M, 1 mmol) for 12 h, the solvent
was removed in vacuo, and the residue was extracted with CH2Cl2 (4 ×
10 ml). The combined CH2Cl2 extracts were washed with brine (15 ml), the
organic fraction was dried (Na2SO4), and the solvent was removed in vacuo.
Recrystallization of the residue from EtOAc gave 18 (0.238 g, 82%); mp 79–
80 °C.– IR (KBr): ν 3120–2522, 1703 cm–1 (CO2H), 1002 (SO).– 1H NMR
(CHCl3-d1): δ 1.26–1.80 [m, 22H, -(CH2)11], 2.32 (t, J = 7.5 Hz, 2H,
COCH2), 2.60 (s, 3H, CH3SO), 2.62–2.86 (m, 2H, SOCH2).
6-Methylsulfonylhexanoic Acid Sodium Salt (25)
Mp 188–190 °C.– Yield 95%.– IR (KBr): ν 1568, 1418 cm–1 (CO2Na),
1269, 1138 (SO2).– 1H NMR (H2O-d2): δ 1.42–1.87 [m, 6H, -(CH2)3], 2.19
(t, J = 7.5 Hz, 2H, CH2CO2Na), 3.00 (s, 3H, CH3SO2), 3.26 (t, J = 8 Hz, 2H,
SO2CH2).
6-Methylsulfonylhexanoic Acid (16)
14-Methylthiotetradecanoic Acid Sodium Salt (26)
Compound 16 was prepared (0.845 g, 87%) using a similar procedure to
that described for the synthesis of 11 above; mp 63–64 °C.– IR (KBr): ν
3150–2550, 1700 cm–1 (CO2H), 1300, 1130 (SO2).– 1H NMR (CHCl3-d1):
δ 1.39–1.49 (m, 2H, CH2), 1.56–1.66 (m, 2H, CH2), 1.75–1.85 (m, 2H, CH2),
2.31 (t, J = 7.5 Hz, 2H, COCH2), 2.82 (s, 3H, CH3SO2), 2.94 (t, J = 7.5 Hz,
2H, SO2CH2).
Mp 240–243 °C (decomp).– Yield 95%.– IR (KBr): ν 1568, 1419 cm–1
(CO2Na).– 1H NMR (H2O-d2): δ 1.27–1.35 [m, 20H, -(CH2)10], 1.50–1.70
(m, 2H, CH2), 2.12 (s, 3H, CH3S), 2.08–2.15 (m, 2H CH2CO2Na), 2.50–2.62
(m, 2H, SCH2).
14-Methylsulfinyltetradecanoic Acid Sodium Salt (27)
14-Methylsulfonyltetradecanoic Acid (19)
Mp 190–191 °C.– Yield 97%.– IR (KBr): ν 1568, 1420 cm–1 (CO2Na),
1022 (SO).– 1H NMR (H2O-d2): δ 1.31–1.78 [m, 22H, -(CH2)11], 2.19 (t, J
= 7.5 Hz, 2H CH2CO2Na), 2.70 (s, 3H, CH3SO), 2.91 (t, J = 7.5 Hz, 2H,
SOCH2).
Compound 19 was prepared (1.35 g, 88%) using a similar procedure to that
described for the synthesis of 11 above; mp 103–104 °C.– IR (KBr): ν
3024–2520, 1698 cm–1 (CO2H), 1302, 1131 (SO2).– 1H NMR (CHCl3-d1):
δ 1.26–1.44 [m, 18H, (CH2)9], 1.58–1.65 (m, 2H, CH2), 1.79–1.87 (m, 2H,
CH2), 2.35 (t, J = 7.5 Hz, 2H, COCH2), 2.90 (s, 3H, CH3SO2), 3.00 (t, J =
7.5 Hz, 2H, SO2CH2).
14-Methylsulfonyltetradecanoic Acid Sodium Salt (28)
Mp 230–233 °C (decomp).– Yield 95%.– IR (KBr): ν 1568, 1420 cm–1
(CO2Na), 1285, 1133 (SO2).– 1H NMR (H2O-d2): δ 1.29–1.57 [m, 20H,
-(CH2)10], 1.76–1.86 (m, 2H, CH2), 2.17 (t, J = 7.5 Hz, 2H CH2CO2Na), 3.08
(s, 3H, CH3SO2), 3.25 (t, J = 7.5 Hz, 2H, SO2CH2).
General Procedure for the Preparation of Methylthio-, Methylsulfinyl-, and
Methylsulfonyl- Alkanoic Acid Sodium Salts (20–28)
A solution of NaOH (20 mg, 0.5 mmol) in H2O (1 ml) was added to a
solution of the respective alkanoic acid (9–11, 14–19, 0.5 mmol) in EtOH
(2 ml), and the mixture was stirred at 25 °C for 1 h prior to removal of the
solvent in vacuo. A warm suspension of compound 22 or 26–28, which are
very sparingly soluble in EtOH, was filtered and the solid product was dried
in vacuo to provide the title compounds. Compounds 20 and 25 were
recrystallized from EtOH. Although compounds 21, 23, and 24 are soluble
in warm EtOH, the slightly cloudy solution that resulted on attempted
recrystallization was filtered, the filtrate was discarded, and the solvent from
the EtOH solution was removed to afford the title product. The physical (mp)
and spectroscopic data (IR, 1H NMR) data for compounds 20–28 are listed
below:
In Vitro Positive Inotropic Effect
Positive inotropic activity was calculated as the percentage increase in
contractile force of isolated guinea pig left atrium, relative to its basal
contractile force in the absence of test compound [19]
.
In Vitro Antifungal Assay
The broth dilution method reported by Barchiesi et al. was used for
determination of minimum inhibitory concentration (MIC values)[20]
.
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298
Iqbal, McEwen, Sardari, Daneshtalab, and Knaus
[11] Y. Liu, J. C. Vederas, J. Org. Chem. 1996, 61, 7856–7859.
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Received: May 16, 2000 [FP490]
Arch. Pharm. Pharm. Med. Chem. 333, 293–298 (2000)